JP2002525275A - Carbapenem antimicrobial compositions and methods of treatment - Google Patents

Abstract

  (57) [Summary] The present invention is a novel 2- (naphthosultamyl) methyl-carbapenem antibacterial agent or a pharmaceutically acceptable salt thereof, combined with other β-lactams, which is useful in the treatment and prevention of enterococcal infection. About things. This combination has not only anti-PBP5 activity but also activity on essential PBPs of sensitive isolates. Thus, the antimicrobial compositions of the present invention make an important contribution to therapies for treating infections caused by difficult-to-control pathogens. This combination is also useful against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and methicillin-resistant coagulase-negative staphylococci (MRCNS).

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND ART [0002] Within the last decade, enterococci have become the second most common pathogen isolated in nosocomial infections. Recent enterococcal isolates (i.e., Enterococcus faecium (E.
faecium), Enterococcus faecalis), due to their ability to rapidly acquire multidrug resistance to all available antimicrobial agents and to propagate resistance determinants through the exchange of genetic elements. The therapeutic dilemma has arisen. Enterococcal antibiotic resistance is characterized according to its sensitivity to two glycopeptides, namely vancomycin (VANCO) and teicoplainin (TEICO), and thus the three main VANCO-resistant enterococci (VRE) ( Phenotypes VanA, VanB and VanC, and possibly even newer types). Enterococcal VanA isolates (E. faecium and E. fae
calis) is resistant to high levels of VANCO and TEICO (MIC ≧ 64 μg / mL, MIC ≧ 16 μg / mL, respectively), and its plasmid transferable resistance can be induced by VANCO and TEICO, however,
B isolates exhibit moderate levels of resistance to VANCO (about 8-64 μg
/ ML), remains sensitive to TEICO (MIC <2 μg / mL)
). VNACO induces resistance to VanB isolates, but it is not considered to be transposable. The phenotype of VanC's VNACO resistance
Enterococcus (E.) has been found in gallinarum and Enterococcus (E.) casseliflavus, which have low levels of resistance to VANCO (MI
C ≧ 4 and ≦ 32 μg / mL), the sensitivity to TEICO is retained (
(MIC ≦ 1 μg / mL).

[0002] VanA-resistant E. faecium (VREF) is a potent β-lactam (cell wall active) system due to the relatively low affinity of its penicillin binding proteins (PBPs), which are important enzymes in cell wall biosynthesis. It is inherently resistant to constituents. β
-Lactam antibiotics inhibit bacterial growth via the binding of bacterial PBP. Enterococci usually contain low-affinity PBP (PBP5), which appears to be overproduced in some recent isolates and may be genetically altered in some cases.

[0003] The emergence of strains that are resistant to most β-lactam, aminoglucoside and quinolone antibiotics when used in monotherapy has led to the isolation of resistance to β-lactam drugs. Only the glycoprotein system remains alone and in combination with aminoglycosides as the first line of defense against the product. For example, the treatment of severe enterococcal infections usually involves the use of a combination of many moderately active β-lactams or aminoglycosides with VANCO. However, this therapeutic option has become increasingly obsolete due to the more recent isolation of enterococcal strains with high levels of resistance to glycopeptides. In addition to the discovery of VRE isolates with high resistance to almost all β-lactam antibiotics (usually occurring after monotherapy), the isolation of enterococci producing β-lactamases, etc. By
There is an increasing need to strengthen research to find new and innovative anti-enterococcal drugs.

DISCLOSURE OF THE INVENTION The present invention relates to β-lactams, aminoglycosides, fluoroquinolones, related quinolones and naphthyridines, chloramphenicol, macrolides,
Novel 2- (naphthosultamyl) methylcarbapenems used in combination with other antibiotics such as ketolides, azalides, Synercid (R), tetracyclines, glycopeptides, novobiocin, oxazolidinones, etc. or combinations thereof It relates to an antibacterial agent or a pharmaceutically acceptable salt thereof. The combination is useful against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and methicillin-resistant coagulase-negative staphylococci (MRCNS).

[0005] The present invention further provides novel 2- (naphthosultamyl) methylcarbapenem antibacterials or pharmaceutically acceptable salts thereof in combination with other β-lactams useful in the treatment and prevention of enterococcal infections. It is also about. The combination has anti-PBP5 activity as well as activity against sensitive PBP in sensitive isolates. Thus, the antimicrobial composition of the present invention greatly contributes to therapy for treating infections caused by these difficult-to-control pathogens.

[0006] Another aspect of the invention relates to the use of novel antibiotic compositions in the treatment of bacterial infections.

[0007]Description of the drawings  FIG. 1 shows VanA-resistant E. faecium CL5053 using a mouse thigh model.
In the treatment, various concentrations alone and in combination with imipenem (20 mg / kg)
The effect of compound A (described below) is shown. Bacterial clearance to CFU
Log₁₀Expressed as a drop.

FIG. 2 shows the Van ^R Gent ^S Amp ^S E. faecalis CL5 of various concentrations of Compound A (described below) alone and in combination with 12 μg / mL gentamicin.
The 244 sterilization rate is shown.

FIG. 3 shows Van ^R Gent ^S Amp ^S E. faecalis of various concentrations of Compound A (described below) alone and in combination with ciprofloxacin at 1.0 μg / mL.
CL4877 sterilization rate is shown.

FIG. 4 shows that Compound A (1) in the treatment of VanA-resistant E. faecium CL5053.
0 mg / kg) and the effects of various amounts of imipenem and meropenem and compound A (10 mg / kg) in combination with various amounts of imipenem or meropenem
) Is shown.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a novel 2- (naphthosultamyl) methyl-carbapenem antibacterial agent used in combination with other β-lactams, aminoglycosides, fluoroquinolones and the like.
U.S. Pat. No. 5,756,725, incorporated herein by reference). The response to a given combination is considered to be strain-specific and is known not to be related solely to the level of susceptibility / resistance to the particular combination. Thus, the combinations of the present invention are intended to be useful for all strains, including those not mentioned herein.

One embodiment of the present invention is directed to a pharmaceutically acceptable carrier; 2- (naphthosultamyl) methyl-carbapenem of formula I:

[0013]

Embedded image [Where R¹Represents H or methyl; CO₂M is a carboxylic acid group, carboxylate anion, pharmaceutically acceptable
Represents a carboxylic acid group protected by an ester group or a protecting group; P represents hydrogen, a hydroxyl group, F or a hydroxyl group protected by a hydroxyl protecting group; each R independently represents -R^*-Q; hydrogen; halogen; -CN;₂; -NR^a R^b; -OR^c; -SR^c; -C (O) NR^aR^b; -C (O) OR^h; -S (
O) R^c; -SO₂R^c; -SO₂NR^aR^b; -NR^aSO₂R^b; -C (O
) R^a; -OC (O) R^a; -OC (O) NR^aR^b; -NR^aC (O) NR^b R^c; -NR^aCO₂R^h; -OCO₂R^h; -NR^aC (O) R^b; Unsubstituted
Or 1 to 4 R^d-Or branched -C substituted with a group_1-6Alkyl;
And unsubstituted or 1-4 R^d-C substituted with a group_3-7Cycloalkyl
Selected from; each R^a, R^bAnd R^cIs independently hydrogen; -R^*, Unsubstituted or 1-4
R^d-Or branched -C substituted with a group_1-6Alkyl; or if unsubstituted
Or 1 to 4 R^d-C substituted with a group_3-7Represents cycloalkyl; or
Is R^aAnd R^bAnd 1 to 3 O, S, NR^cBy
Represents a 4- to 6-membered saturated ring which may be interrupted;^cIs as defined above
—C (O) —; the ring is unsubstituted or has 1 to 4 RⁱSubstituted with a group
Or R^bAnd R^cAnd one or more O, S, NR together with the intervening atom^aInterrupted by
Represents a 4- to 6-membered saturated ring which may be substituted;^aIs as defined above-
The ring is unsubstituted or 1 to 4 RⁱEach R^dIs independently halogen; -CN; -NO₂; -NR^eR^f; -OR^g;-
SR^g; -CONR^eR^f; -COOR^g; -SOR^g; -SO₂R^g; -SO ₂ NR^eR^f; -NR^eSO₂R^f; -COR^e; -NR^eCOR^f; -OCO
R^e; -OCONR^eR^f; -NR^eCONR^fR^g; -NR^eCO₂R^h;-
OCO₂R^h; -C (NR^e) NR^fR^g; -NR^eC (NH) NR^fR^g;-
NR^eC (NR^f) R^g; -R^*Or -Q; R^e, R^fAnd R^gIs hydrogen; -R^*Unsubstituted or 1-4 RⁱBased on
Substituted straight-chain or branched -C_1-6Represents alkyl; or R^eAnd R^fAnd 1-3 atoms of O, S, -C (O)-or
Is NR^gRepresents a 4-6 membered saturated ring optionally interrupted by^gIs above
As defined; the ring is unsubstituted or has 1 to 4 RⁱEach RⁱIs independently halogen; -CN; -NO₂Phenyl; -NHSO₂R^h ; -OR^h; -SR^h; -N (R^h)₂; -N⁺(R^h)₃; -C (O) N (R ^h )₂; -SO₂N (R^h)₂Heteroaryl; heteroarylium; -CO ₂ R^h; -C (O) R^h; -OCOR^h; -NHCOR^hGuanidinyl; cal
Bamimidyl; or represents ureido; each R^hIs independently hydrogen, linear or branched -C_1-6Alkyl group, -C_{3- 6} R represents a cycloalkyl group or phenyl;^hThere are two groups
If those R^hOne or two O, S, SO₂, −
C (O)-, NH and NCH₃4-6 member saturation that may be interrupted by
Q can be selected from the group consisting of:

[0014]

Embedded image a and b are 1, 2 or 3; L⁻Is a pharmaceutically acceptable counterion; α is O, S or NR^sRepresents β, δ, λ, μ and σ are CR^t, N or N⁺R^sWhere N⁺R ^s Is not more than one of β, δ, λ, μ and σ; R^*Is

[0015]

Embedded imageIs selected from the group consisting of: d is O, S or NR^kE, g, x, y and z are CR^m, N or N⁺R^kWhere N⁺R ^k Is no more than one of e, g, x, y and z; R^kIs hydrogen; unsubstituted or 1-4 RⁱStraight or branched substituted with a group
C_1-6Alkyl; or-(CH₂)_nQ (n = 1, 2 or 3;
Q is as defined above); each R^mIs independently hydrogen; halogen; -CN; -NO₂; -NRⁿR^o; -OR ⁿ ; -SRⁿ; -CONRⁿR^o; -COOR^h; -SORⁿ; -SO₂Rⁿ;
-SO₂NRⁿR^o; -NRⁿSO₂R^o; -CORⁿ; -NRⁿCOR^o;-
OCORⁿ; -OCONRⁿR^o; -NRⁿCO₂R^h; -NRⁿCONR^oR ^h ; -OCO₂R^h; -CNRⁿNR^oR^h; -NRⁿCNHNR^oR^h; -N
RⁿC (NR^o) R^hUnsubstituted or 1-4 RⁱStraight chain substituted with a group
-B of branch_1-6Alkyl; unsubstituted or 1-4 RⁱSubstituted with a group
Linear or branched -C_3-7Cycloalkyl; or-(CH₂)_nQ (n
And Q are as defined above); RⁿAnd R^oIs hydrogen, phenyl; unsubstituted or 1-4 RⁱSubstituted with a group
Straight-chain or branched -C_1-6Represents an alkyl; each R^sIs independently hydrogen; unsubstituted or 1-4 RⁱSubstituted with phenyl
Or a linear or branched -C_1-6Represents an alkyl; each R^tIs independently hydrogen; halogen; phenyl; -CN;₂; -NR^uR ^v ; -OR^u; -SR^u; -CONR^uR^v; -COOR^h; -SOR^u; -S
O₂R^u; -SO₂NR^uR^v; -NR^uSO₂R^v; -COR^u; -NR^uC
OR^v; -OCOR^u; -OCONR^uR^v; -NR^uCO₂R^v; -NR^uC
ONR^vR^w; -OCO₂R^vUnsubstituted or 1-4 RⁱSubstituted with a group
Linear or branched -C_1-6R represents alkyl;^uAnd R^vIs hydrogen or unsubstituted or 1-4 RⁱSubstituted with a group
Linear or branched -C_1-6Represents alkyl; or R^uAnd R^vAnd one or more O, S, NR together with the intervening atom^wOr -C
Represents a 4- to 6-membered saturated ring which may be interrupted by (O)-;
Or 1 to 4 RⁱEach R^wIs independently hydrogen; unsubstituted or 1-4 RⁱDirectly substituted with a group
Chain or branched -C_1-6Alkyl; 1-4 RⁱMay be substituted with a group
C_3-5Cycloalkyl; 1-4 RⁱOptionally substituted with a group
Or 1-4 RⁱRepresents heteroaryl optionally substituted with a group;
Or R^hAnd R^wAnd one or two O, S, SO₂, N
H or NCH₃Represents a 5-6 membered saturated ring optionally interrupted by^xIs hydrogen or one or two O, S, SO, SO₂, NR^w, N⁺ R^hR^wOr a straight or branched chain which may be interrupted by -C (O)-
C_1-8Alkyl; the alkyl chain is unsubstituted or has 1 to 4 halogen atoms;
, CN, NO₂, OR^w, SR^w, SOR^w, SO₂R^w, NR^hR^w, N⁺ (R^h)₂R^w, -C (O) -R^w, C (O) NR^hR^w, SO₂NR^hR^w,
CO₂R^w, OC (O) R^w, OC (O) NR^hR^w, NR^hC (O) R^w, N
R^hC (O) NR^hR^wOr substituted with phenyl or heteroaryl
Said phenyl or heteroaryl has 1 to 4 RⁱGroup or 1-2
Linear or branched C_1-3An alkyl group (the alkyl group is unsubstituted or
RⁱR.^yAnd R^zIs hydrogen; phenyl; unsubstituted or 1-4 RⁱSubstitute with group
O, S, NR^w, N⁺R^hR^wOr interrupted by -C (O)-
Linear or branched -C which may be_1-6Represents alkyl; or R^yAnd R^zTogether with the intervening atoms, O, S, SO₂, NR^w, N⁺R^h R^wOr a 4- to 6-membered saturated ring which may be interrupted by -C (O)-
The ring is unsubstituted or has 1 to 4 RⁱR;^xAnd R^yAnd when taken together represent a 4- to 6-membered ring as defined above,^zIs
As defined above, or R^zIs an integrated R^xAnd R^yBy
Represented O, S, NR^wOr to a ring which may be interrupted by -C (O)-
Represents another saturated 4- to 6-membered ring fused; the rings may be unsubstituted or 1 to 4 R ⁱ Substituted with a group. And carbapenems, cephalosporins (ceftriaxone), penici
Phosphorus; aminoglycosides (eg, gentamicin and amikacin, dibeca)
Syn, streptomycin, neomycin, kanamycin, spectinomycin
, Kasugamycin, etc., but not limited thereto);
(Eg, ciprofloxacin and trovafloxacin),
Sparfloxacin, gatifloxacin,
Grepafloxacin, ofloxacin, norfloxacin,
Loxin, levofloxacin, etc. (limited to these
)) And related quinolones having activity against topoisomerase
And naphthyridines; chloramphenicol; and macrolides, ketori
, Azalides (and other related polyketides), sinacide (registered trademark)
), Tetracyclines (glycylcyclines, etc.), glycopeptides (Banco
Mycin, teicoprimin, LY-333328 and the like (including but not limited to these)
)), Novobiocin (and coomamycin) and oxazolidino
Compositions containing other antibiotics, such as antibiotics or combinations thereof.
You.

The invention is described in detail herein using the terms defined below, unless otherwise indicated.

[0017] The carbonate carboxylate anion, radical -COO having a negative charge ^- refers to.

The term “alkyl” refers to a group having 1 to 10 carbon atoms unless otherwise specified.
Refers to monovalent alkanes (hydrocarbons) that are derived. It can be linear, branched or cyclic
May be. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl
Butyl, t-butyl, cyclopentyl and cyclohexyl. Place
When substituted, the alkyl group is at the possible point of attachment,^dAnd R ⁱ And may be substituted with up to four substituents selected from Alkyl group is Al
When referring to a group substituted with a kill group, the expression is used interchangeably with "branched alkyl group".
Used.

Cycloalkyl is an alkyl group having 3 to 15 carbon atoms that does not have alternating double bonds between carbon atoms, that is, a resonant double bond. The group may have from 1 to 4 fused rings.

The term “alkenyl” refers to a straight, branched or cyclic hydrocarbon group having 2 to 10 carbon atoms and having one or more carbon-carbon double bonds. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

The term “alkynyl” refers to a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms and having one or more carbon-carbon triple bonds. Preferred alkynyl groups include ethynyl, propynyl and butynyl.

Aryl refers to aromatic rings such as phenyl and substituted phenyl, as well as fused rings such as naphthyl and phenanthrenyl. Thus, an aryl group has one or more rings of 6 or more atoms; up to 5 such rings;
Not more than two; alternating (resonant) between adjacent carbon atoms or suitable heteroatoms
There is a double bond. Preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined above. Preferred substituted aryls include phenyl and naphthyl.

The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon group of 5 or 6 ring atoms or a bicyclic aromatic group of 8 to 10 atoms, wherein one or more Having the atoms O, S or N, a carbon atom or a nitrogen atom being the point of attachment,
One or two other carbon atoms may be replaced by a heteroatom selected from O or S, and refers to a group in which one to three other carbon atoms may be replaced by a nitrogen heteroatom, Heteroaryl groups may be substituted as described above. Examples of this class include pyrrole, pyridine, oxazole, thiazole and oxazine. With the first nitrogen and oxygen or sulfur,
Another nitrogen atom may be present to form, for example, a thiadiazole. Examples include:

[0024]

Embedded image

Heteroarylium refers to a heteroaryl group having a quaternary nitrogen atom and thus having a positive charge. Examples include:

[0026]

Embedded image

When a ring having one or more additional nitrogen atoms displays a charge on a particular nitrogen atom, the charge may be on a different nitrogen atom in the ring due to the resulting charge resonance. It is clear.

[0028]

Embedded image

The term “heterocycloalkyl” means that one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and up to three other carbon atoms are replaced by a heteroatom. Refers to a cycloalkyl group (non-aromatic) which may be substituted.

The terms “quaternary nitrogen” and “positive charge” refer to a tetravalent positively charged nitrogen atom, for example, a tetraalkylammonium group (eg, tetramethylammonium), a heteroarylium (eg, : N-methylpyridinium), physiological pH
And basic nitrogen that has been protonated with. Thus, cationic groups include positively charged nitrogen-containing groups as well as basic nitrogen protonated at physiological pH.

The term “heteroatom” means O, S or N independently selected.

Halogen and “halo” refer to bromine, chlorine, fluorine and iodine.

Alkoxy refers to C ₁ -C ₄ alkyl-O—, where the alkyl group may be substituted as described herein.

When a group is said to be “substituted,” unless otherwise stated it means that the group has 1-4 substituents. For R, R ^a , R ^b and R ^c , the substituents available on the alkyl group are selected from the possible forms of R ^d . Many of the variable groups may be substituted by up to four R ⁱ groups. With respect to R ^e , R ^f and R ^g , when they represent substituted alkyl, the substituents available on the alkyl are selected from the possible forms of R ⁱ .

When a functional group is said to be “protected,” it is meant that the group is modified to prevent undesired side reactions at the protected site.
Suitable protecting groups for the compounds of the present invention are determined by Greene, TW et al., Protective Groups in Organic Synthesis Wiley, taking into account the state of the art.
Reference to standard books, such as New York (1991)), will be apparent from the present application. Examples of suitable protecting groups are given throughout this specification.

In some of the carbapenem compounds of the present invention, M is a readily removable carboxyl protecting group, or P represents a hydroxyl group protected by a hydroxyl protecting group. Such conventional protecting groups consist of known groups used to protectively block hydroxyl or carboxyl groups during the synthetic procedures described herein.
Those conventional blocking groups are easily removable. That is, those groups can be removed as desired by methods that do not cause cleavage or other disruption of other portions of the molecule. Such methods include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with transition metal catalysts and nucleophiles, and catalytic hydrogenation.

Examples of carboxyl protecting groups include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl ,
Examples include p-nitrobenzyl, 4-pyridylmethyl and t-butyl.

Examples of suitable C-6 hydroxyethyl protecting groups include triethylsilyl, t-
Butyldimethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl,
There are t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.

The carbapenems of the present invention other than the above-mentioned novel 2- (naphthosultamyl) methyl-carbapenems include imipenem (± cilastatin), meropenem, biapenem, panipenem, (4R, 5S, 6S) -3- [3S
, 5S) -5- (3-Carboxyphenylcarbamoyl) pyrrolidin-3-ylthio] -6- (1R) -1-hydroxyethyl] -4-methyl-7-oxo-1
-Azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, its enantiomers, diastereomers or pharmaceutically acceptable salts.

The β-lactams included in the present invention include imipenem (± cilastatin; those containing cilastatin = Primaxin (registered trademark), meropenem, biapenem, panipenem, (4R, 5S, 6S) -3- [
3S, 5S) -5- (3-Carboxyphenylcarbamoyl) pyrrolidine-3-
Ilthio] -6- (1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, its enantiomer, diastereomer And carbapenems such as pharmaceutically acceptable salts; cefoperazone, cefotiam, cefpirom, cefmetazole, cafazolin, cephalexin, cefuroxime, cefaclor, cefotaxime, ceftriaxone, moxalactam, cefixoxime, and other cephalosporins; Cefamycins; penicillins such as ampicillin, amoxicillin, piperacillin, nafcillin, oxacillin, cloxacillin; and β-lactamase inhibitors and penicillins such as sulbactam, clavulanic acid, tazobactam and the like. Combination, and the like.

The carbapenem compositions of the present invention, as such, and in the form of pharmaceutically acceptable salts and esters, are useful for treating bacterial infections in animal and human patients. The term "pharmaceutically acceptable esters, salts or hydrates" refers to salts, esters and hydrates of the compounds of the present invention which would be apparent to a pharmaceutical chemist.
That is, they are substantially non-toxic and can favorably affect the pharmacokinetic properties of the compound, such as palatability, absorption, distribution, metabolism and excretion. Other factors that are also important in the selection, and more practical aspects, are the raw material cost, crystallinity, yield, stability, solubility, hygroscopicity, and flowability of the resulting drug substance. is there. Conveniently, a pharmaceutical composition can be formulated by combining the active ingredient with a pharmaceutically acceptable carrier. Therefore, the present invention also relates to a pharmaceutical composition using a novel carbapenem compound as an active ingredient and a method for treating bacterial infection.

—CO ₂ M attached to the carbapenem nucleus at the 3-position is a carboxylic acid group (M represents H), a carboxylate anion (M represents a negative charge), a pharmaceutically acceptable ester ( M represents an ester-forming group) or a carboxylic acid protected by a protecting group (M represents a carboxyl protecting group).

The above pharmaceutically acceptable salts can take the form —COOM, where M
Is a negative charge and the charge is balanced by a counter ion such as an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable counterions can be calcium, magnesium, zinc, ammonium or alkylammonium cations, such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine,
And triethanolhydroammonium.

The pharmaceutically acceptable salts also include the acid addition salts. Thus, the compounds of the formula I can be used in the form of salts derived from inorganic or organic acids. Such salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, Cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrogen bromide Acid salt, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectic acid Salt, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and the like There is such a fine undecanoate.

Pharmaceutically acceptable esters are those that would be readily apparent to a medicinal chemist, such as those described in detail in US Pat. No. 4,309,438. Such pharmaceutically acceptable esters include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl as well as those that hydrolyze under physiological conditions such as those described in detail in US Pat. No. 4,479,947. There are things that are done. They are also referred to as "biolabile esters".

Biolabile esters are hydrolysable in vivo and may be suitable for oral administration due to good absorption from the gastric or intestinal mucosa, resistance to gastric acid degradation and other factors. Examples of in vivo unstable esters include those wherein M is an alkoxyalkyl group, an alkylcarbonyloxyalkyl group, an alkoxycarbonyloxyalkyl group, a cycloalkoxyalkyl group, an alkenyloxyalkyl group, an aryloxyalkyl group, an alkoxyaryl group, an alkylthioalkyl group. , A cycloalkylthioalkyl group, an alkenylthioalkyl group, an arylthioalkyl group or an alkylthioaryl group. These groups may be substituted at their alkyl or aryl moieties by acyl or halo groups. Examples of in vivo unstable ester forming moieties include M is acetoxymethyl,
1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl, 1
-Isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl) methyl.

L ⁻ may be present or absent as needed to maintain proper charge balance. If there L ^- represents a pharmaceutically acceptable counterion. Most anions derived from inorganic or organic acids are suitable. Representative examples of such counterions include acetic acid, adipic acid, aminosalicylic acid, methylene citric anhydride, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, bromine, citric acid, camphoric acid, camphorsulfonic acid , Chlorine, estolate, ethanesulfonic acid, fumaric acid, glucoheptanic acid, gluconic acid, glutamic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, pantothenic acid, pectic acid, phosphoric acid / Diphosphoric acid, polygalacturonic acid, propionic acid,
There are salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid and tosylate ions. Other suitable anionic species will be apparent to those of ordinary skill in the art.

Similarly, when L ⁻ is malonic acid, tartaric acid or ethylenediaminetetraacetic acid (EDT
When representing multiple negatively charged species, such as ions of A), an appropriate number of carbapenem molecules may associate therewith to maintain overall charge balance and neutrality.

It is preferred that at least one of the R groups bonded to the naphthosultam skeleton has a positively charged portion. Thus, it may include -R ^* or Q, and thus a moiety having a positively charged group.

Yet another embodiment of the present invention is realized when the compound of structural formula I is a compound represented by formula Ie: or a pharmaceutically acceptable salt thereof.

[0051]

Embedded image Wherein, R, -R *, it has a positive charge moiety selected from the group consisting of C _1-6 alkyl chain linear or branched substituted by ^Q and one R ^d group; Rd is independently Is selected from -R ^* or Q; Q is selected from the group consisting of:

[0052]

Embedded image

Where L⁻, A and b are as defined above; R^xIs hydrogen or 1
Or two O, S, SO, SO₂, NR^w, N⁺R^hR^wOr -C (
O)-a linear or branched C which may be interrupted by-_1-8Alkyl
A moiety selected from the group consisting of: unsubstituted or 1-4 alkyl chains.
Halogen, CN, NO₂, OR^w, SR^w, SOR^w, SO₂R^w, NR^hR ^w , N⁺(R^h)₂R^w, -C (O) -R^w, C (O) NR^hR^w, SO₂NR ^h R^w, CO₂R^w, OC (O) R^w, OC (O) NR^hR^w, NR^hC (O)
R^w, NR^hC (O) NR^hR^wOr a phenyl or heteroaryl group
Substituted; the phenyl or heteroaryl has 1 to 4 RⁱBase
Represents one or two linear or branched C_1-3An alkyl group (the alkyl group is unsubstituted
There are 1 to 4 RⁱR.^*Is selected from:

[0054]

Embedded image Wherein d represents NR ^k ; R ^k represents straight-chain or branched —C _1-6 alkyl; e, g, x and y represent CR ^m or N ⁺ R ^k , wherein R ^k is as ^defined above. As defined, R ^m represents hydrogen.

In still another embodiment of the present invention, wherein the compound of formula I is (1S, 5R, 6S) -2- (5-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2. 2] oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; 1S, 5R, 6S) -2- (5-(((3-hydroxyprop-1-yl)
-1,4-diazoniabicyclo [2.2.2] oct-1-yl) methyl) (1
, 8-Naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (5-((1-methylimidazole-3-ium) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate; (1S, 5R, 6S) -2- (5-(((2- (1-methyl Imidazole-3
-Ium) -ethyl) (1,8-naphthosultam) methyl) -6- [1 (R)-
(Hydroxyethyl) -1-methylcarbapene-2-em-3-carboxylate; (1S, 5R, 6S) -2- (4-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2] .2] oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl) -1,
4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,
8-Naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (4- ( 2-(((3-hydroxyprop-1-
Yl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1 -Methylcarbapene-2-em-3-carboxylate chloride;
Or (1S, 5R, 6S) -2- (4- (2-((1-methylimidazole-3-
(Ium) -ethyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate.

In a preferred embodiment of the present invention, a compound of formula I is selected from the group consisting of (1S, 5R, 6S) -2- (5-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] ] Oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; (1S , 5R, 6S) -2- (4-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl) methyl) (1,8-naphthosultam) methyl)- 6- [1 (R) -hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate chloride; or (1S, 5R, 6S) -2- (4- (2-(((carbamoyl Methyl) -1,
4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,
8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride.

In another preferred embodiment of the invention, the other antibiotic used is cephalosporins, penicillins, gentamicin, ciprofloxacin, imipenem, meropenem, chloramphenicol, vancomycin or teicoprimin Is realized when selected from the group consisting of

In yet another aspect of the present invention, the novel antimicrobial composition of the present invention comprises a pharmaceutically acceptable carrier; a therapeutically effective amount of (1S, 5R, 6S) -2- (5-(((( Carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1- Methylcarbapene-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (4-((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct -1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; and (1S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl) -1,
4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,
2- (naphthosultamyl) methyl-carbapenem selected from 8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; and carbapenem , Cephalosporins (ceftriaxone), penicillins; aminoglycosides (
Examples: gentamicin and amikacin, dibekacin, streptomycin, neomycin, kanamycin, spectinomycin, kasugamycin, and the like, but not limited thereto; fluoquinolones (eg, ciprofloxacin and trovafloxacin, sparflor) Chloramphenicol, including, but not limited to, soxacin, gatifloxacin, grepafloxacin, ofloxacin, norfloxacin, phloxine, levofloxacin, and related quinolones and naphthyridines having activity against topoisomerase; And macrolides, ketolides, azalides (and other related polyketides), Sinaside®, tetracyclines (such as glycylcyclines), sugar peptides Earth (vancomycin, teichoic plies Nin, LY-333
328 (including but not limited to), novobiocin (and coomamycin) and oxazolidinones or a combination thereof, in a therapeutically effective amount of another antibiotic.

In one embodiment of the present invention, 2- (naphthosultamyl) methyl-carbapenem is (1S
, 5R, 6S) -2- (4- (2-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8- Naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate chloride; other antibiotics are cephalosporins, penicillins, Gentamicin, ciprofloxacin,
Imipenem, meropenem, (4R, 5S, 6S) -3-[(3S, 5S) -5
(3-carboxyphenylcarbamoyl) pyrrolidin-3-ylthio] -6- (
1R) -1-Hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, chloramphenicol, vancomycin and teicoprimin It is realized when it is done.

Another embodiment of the present invention is directed to a 2- (naphthosultamyl) methyl-carbapenem antibacterial agent or an ophthalmically acceptable salt thereof in combination with the other carbapenems described above.

One aspect of the present invention is that the other carbapenem contains from about 1 to about 100 mg / kg, preferably from about 2 to about 50 mg / kg of (4R, 5S, 6S) -3-[(3S, 5S) -5.
-(3-Carboxyphenylcarbamoyl) pyrrolidin-3-ylthio] -6-
(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, imipenem or meropenem; 2- (naphthosultamyl) About 0.1 to about 5 methyl-carbapenems
0 mg / kg, preferably about 0.5 to about 20 mg / kg of (1S, 5R, 6S)
-2- (4- (2-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8-naphthosultam) methyl)- Realized when it is 6- [1 (R) -hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate chloride.

Another embodiment of the present invention relates to a novel 2- (naphthosultamyl) methyl-carbapenem antibacterial agent or an ophthalmic thereof as described above in combination with fluoroquinolones, aminoglycosides or chloramphenicol or a combination thereof. Pertains to salts that are acceptable.

One aspect of the invention is that the fluoroquinolone is ciprofloxacin at about 0.1 to about 40 mg / kg, preferably about 0.5 to about 20 mg / kg, and the aminoglycoside is at about 0.5 to about 40 mg / kg. Gentamicin at 12 mg / kg, and 2- (naphthosultamyl) methyl-carbapenem at about 0.1 to about 50 mg / kg, preferably about 0.1 mg / kg.
5 to about 20 mg / kg of (1S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl)). ) -Ethyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride.

[0064] Yet another embodiment of the present invention relates to an imipenem or meropenem and another antibiotic selected from cephalosporins, penicillins, gentamicin, ciprofloxacin, chloramphenicol, vancomycin or teicoprimin. The present invention relates to a novel 2- (naphthosultamyl) methyl-carbapenem antibacterial agent or an ophthalmologically acceptable salt thereof as described above.

The compositions of the present invention are valuable as antimicrobial agents that are active against enterococcal infections, especially clinical isolates of multidrug resistant E. faecium. The compositions of the present invention are also valuable as active antimicrobial agents against various Gram-positive and Gram-negative bacteria. Many of the compositions of the present invention are also physiologically active against MRSA / MRCNS.

Patients suitable for administering the formulations of the present invention include mammals, primates, humans and other animals. When administering the composition to a mammal infected with a susceptible bacterium,
In vivo activity is expected from in vitro antibacterial activity.

Performing a standard susceptibility test shows that the compositions of the invention are active against MRSA and enterococcal infections.

The compounds of the present invention can be formulated into pharmaceutical compositions by combining the compounds with a pharmaceutically acceptable carrier. Examples of such carriers are described below.

The compounds of the present invention can be used in powder or crystalline form, solution or suspension. They can be administered by various means, and particularly important are local administration, oral administration and intraperitoneal administration by injection (intravenous or intramuscular injection).

Compositions for injection, the preferred route of administration, may be formulated in unit-dose in ampoules or in multi-dose containers. Injectable compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain various pharmaceutical agents. Alternatively, the active ingredient may be in powder (lyophilized or non-lyophilized) form and reconstituted with a suitable vehicle at the time of administration, such as sterile water. For injectable compositions, typically the carrier will include sterile water, saline or another injectable liquid such as, for example, peanut oil for intramuscular injection. Further, various buffers, preservatives, and the like can be contained.

Formulations for topical administration may be made by forming an ointment, cream, lotion in a carrier such as a hydrophobic or hydrophilic base; by forming a coating in an aqueous, oily or alcoholic liquid; Alternatively, it can be performed by forming a powder in a dry diluent.

The compositions for oral administration can take the form of tablets, capsules, oral suspensions and oral solutions. The oral composition can use carriers such as conventional pharmaceutical preparations, and can be given a sustained release or a rapidly transportable preparation.

The dosage to be administered is highly dependent on the condition and size of the patient to be administered, the route and frequency of administration, the susceptibility of the pathogen to the particular compound chosen, the virulence of the infection, and other factors. However, these should be left to the discretion of the physician in accordance with dosage standards well known in the antimicrobial art.
Aside from the nature of the infection and the peculiar identity of the recipient, another factor that affects the precise mode of administration is the molecular weight of the compound.

The novel antibiotic compositions of this invention for human administration, whether liquid or solid, can range from as high as about 0.01% to about 99% per unit dose (preferably about 10%). 2- (naphthosultamyl) methyl-carbapenem as described herein and from about 1% to about 99.99% (preferably from about 40% to about 9%).
0%) of one or more other antibiotics, such as those described herein.
The composition typically comprises from about 125 mg to about 3.0 g of the 2- (naphthosultamyl) methyl-carbapenems described herein, but generally from about 250 mg to 100 mg.
Using a dose in the range of 0 mg, about 20 mg for the other antibiotics described herein
It is preferred to use a dosage of 0 mg to about 5 g, preferably about 250 mg to about 1000 mg. For intraperitoneal administration, the unit dose is pure compound in a sterile aqueous solution,
Or they are usually contained in the form of soluble powders for liquids,
H and can be adjusted to isotonic.

The invention described herein provides a method of treating a bacterial infection in a mammal in need of treatment of the bacterial infection, comprising administering the claimed composition in an amount effective to treat the infection to the mammal. And administering to the subject.

Preferred modes of administration of the claimed compositions include oral and intraperitoneal administration, such as intravenous infusion, intravenous bolus and intramuscular injection, wherein the unit dose is a therapeutically effective amount of each active ingredient. Or formulated to contain any fractional amount thereof.

For adults, about 5 to 50 mg / kg, preferably about 250 mg to about 1000 m
g / person of 2- (naphthosultamyl) methyl-carbapenem antimicrobial compound and about 250
It is preferred to administer from mg to about 1000 mg / person of the other antibiotic one to four times daily. More specifically, in the case of mild infection, administration of about 250 m 2 or 3 times a day
g of the 2- (naphthosultamyl) methyl-carbapenem antimicrobial compound and about 250 mg of another antibiotic twice or three times daily are desirable. For moderate infections against highly sensitive gram-positive bacteria, approximately 500 mg of 2- (naphthosultamyl) methyl-carbapenem and the other antibiotics three or four times daily, respectively.
Is desirable. For severe and life-threatening infections of microorganisms with an upper limit of antibiotic susceptibility, 2- (naphthosultamyl) methyl-carbapenem and other antibiotics can be administered about 500-2000 three or four times daily, respectively.
A dose of mg may be desirable.

For children, a dose of about 5 to 25 mg / kg, preferably 2 to 3 or 4 times a day, typically 10 mg / kg, is desirable.

The claimed composition contains a broad class of antibiotics known as carbapenems. Many carbapenems are dehydropeptidase (DHP)
Vulnerable to attack by kidney enzymes known as. The attack or degradation can reduce the efficacy of the carbapenem antimicrobial. On the other hand, many of the compounds of the present invention
It may be relatively less susceptible to such attacks and therefore may not require the use of DHP inhibitors. However, such uses are made as appropriate and are contemplated as part of the present invention. DHP inhibitors and their use with carbapenems
For example, European Patent Application 791022616.4 (Patent No. 0007614) filed on July 24, 1979 and 82107174 filed on August 9, 1982.
. No. 3 (Publication No. 0072014).

If DHP inhibition is desired or necessary, the compositions of the present invention can be combined or combined with a suitable DHP inhibitor as described in the above-mentioned patents and published applications. In the above cited European patent application, the DH of the carbapenems of the present invention is described.
Methods for measuring P sensitivity are described, and suitable inhibitors, combination compositions and methods of administration are disclosed. It is preferred to administer a pharmaceutically acceptable amount of cilastatin together with the carbapenems. The preferred weight ratio of DHP: DHP inhibitor to carbapenem in the combination composition is about 1: 1. The amount of DHP used can be determined by one skilled in the art. U.S. Pat. No. 4,539,208, which is incorporated herein by reference, indicates the amount of DHP that can be used with carbapenem.

A preferred DHP inhibitor is 7- (L-2-amino-2-carboxy-ethylthio) -2- (2,2-dimethylcyclopropanecarboxamide) -2-heptenoic acid or a useful salt thereof. . Therefore, another embodiment of the present invention relates to a method for preparing the above-mentioned 2- (naphthosultamyl) methyl-carbapenem antibacterial agent or an ophthalmically acceptable salt thereof, using 7- (L-2-amino-2-carboxy-ethylthio) -2. This is realized when used in combination with imipenem or meropenem containing-(2,2-dimethylcyclopropanecarboxamide) -2-heptenoic acid or a useful salt thereof.

Hereinafter, the present invention will be further described with reference to examples, but the present invention is not limited to these examples.

[0083]Example 1  (1S, 5R, 6S) -2- (4- (2- (
((Carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct
-1-yl))-ethyl) (1,8-naphthosultam) methyl) -6- [1 (R
) -Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxyle
Chlorate (compound A) is used to clear CL5053 from local soft tissue (thigh).
The relative in vivo protective ability that affects
It was measured with a model. Multiple antibiotic administrations over 5 days (subcutaneous)
. Tissues were aseptically removed at +7 days and processed.

[0084]Materials and methods  Local tissue infection modelPreparation of bacterial culture  Original culture of E. faecium CL5053 (obtained from Bellevue Hospital, NYC)
Was obtained from slants or L-tubes. Trypticase soy broth (TSB) approx. 75
Inoculate about 1 mL of the seed culture into a shake flask containing
Shake at 250 rpm over time. Wash the culture (ie Sorval
l Centrifuge at 5000 rpm in RC-5B for about 15 minutes to remove bacterial cells
Original volume in fresh TSB containing serine (or PBS-10% glycerin)
By regenerating the pellet in about half volume, it was concentrated twice [about 10 times.⁹-10¹⁰Colony
-Forming unit (CFU / mL)]. Finally, about 1 mL of the washed original culture solution was added to -7 mL.
Stored at 0 ° C. for later use in performing cultures for animal infection.

Prior to infection, 1 mL of the frozen culture was thawed with cold H ₂ O and heated to 35
C., added to about 75 mL of fresh TSB, and incubated for about 10 hours at 35.degree. C. as described above. The 10 hour culture was washed as above to remove media containing cell growth and toxicants released upon bacterial death. The cell pellet was regenerated with fresh TSB in half the original volume. 0.2 mL of the washed and concentrated culture solution (load inoculum) was injected intramuscularly (im) into the right thigh of the mouse. Infected mice were further divided into appropriate groups of 5 or 10 animals for each antibiotic dose.

[0086]Preparation of antibiotics  The antibiotic of the present invention is prepared by adding 10 mM of 3-[-morpholinolpropanesulfonic acid
(MOPS) prepared in buffer, pH 7.1. About all carbapenems
However, regardless of the antibiotic concentration, a final dose of 40 mL at 0.5 mL / mouse of inoculum was used.
g / kg at a concentration to prevent renal dehydropeptidase-I (DHP-1) inhibition.
The harmful agent, cilastatin, is also contained in the MOPS buffer. 1 from bacterial load
Hours later (+1 hour), antibiotic administration (0.5 mL subcutaneous administration) is started, and then
Two doses were given at time intervals (+5 and +9 hours). Then about +20: 00
Once or twice a day (about 10-12
And about 24 hour intervals) and antibiotics for a total of 8 or 13 doses
Was continued. Two days after the last antibiotic dose (+7 days), the animals were sacrificed and
Thigh tissue was obtained and subjected to CFU measurement.

[0087]animal  Random outbred CD1 mice (Charles River Labs) were given a final concentration of 250 mg /
Cyclophosphamide (Cytoxan) prepared in PBS at kg / 0.5 mL / mouse
) Was rendered immunocompromised by a single injection, and about 4 days later E. faecium CL50
A 53 intramuscular bacterial load was performed. 0.45μ just before or after bacterial load
m membrane filtered ferric iron (Fe⁺³) / PBS solution 0.5mL at 20mg / kg
Intracavitary injection. Fe⁺³The source was ferric ammonium citrate (18.5% by weight).
Fe⁺³Appropriate solubilization in PBS followed by intraperitoneal administration during bacterial challenge
Obtained by filtration through a 0.45 μm membrane immediately before.

[0088]Tissue preparation for detection of colony forming units (CFU)  On day +7, the mice were sacrificed by euthanasia and the lower abdomen and thighs were 70% ethanol.
And the outer skin was aseptically removed. The exposed femoral tissue is aseptically collected and sterile PBS
Into a test tube containing 4 mL of / 10% glycerin, and temporarily store at −70 ° C. or
Same day processing. On the day of the plate culture, place the frozen thigh in cold H₂Thaw with O and polytron (
Pulverize for 5-10 seconds using a homogenizer and place on ice
Further dilution. 10-fold serial dilutions of each sample were chilled with fresh TSB0.
Prepared in a 9 mL test tube and then placed on an enterococci-specific m-enterococcal agar plate
0.1 mL from selected dilution tubes were plated. Plate for 2-3 days
After incubation at 35 ° C., the number of CFU remaining per thigh was determined.

[0089]result  Figure 1 shows that Compound A alone effectively protects mice (40,
At 20, 10 and 5 mg / kg, respectively, 3.3, 2.08, about 0.8 and
0.6 vs. CFU reduction). However, a certain amount of IPM (20 mg / kg
) And Compound A had a significant synergistic effect (eg, 20 mg / kg
Of the effective logarithmic clearance of Compound A at 5 mg / kg was 0.6
From the number to 2.75 log).

[0090]Example 2  Combination of Gentamicin and Compound A is Van^RGent^SAmp^S(R = resistance
E. faecalis CL5244 (Washington University)
 School of Medicine, St. Louis, MO)
To do this, a partial cross synergistic effect test was performed, followed by a time-kill test.

The combination of Ciprofloxacin and Compound A was combined with Van ^R Gent ^S Amp ^S (R =
Resistant and S = sensitive) E. faecalis CL4877 (University of Mar
yland Hospital, University of Maryland Medical System, 22 South Green St
, Baltimore, MD 21201), a partial cross-synergy test was performed, followed by a time-kill test.

[0092]Materials and methods  Antibiotics  A compound A stock solution was prepared in 10 mM MOP buffer (pH 7.0), and its concentration was adjusted.
The degree was confirmed using spectrophotometric analysis. Gentamicin (Sigma Chemical Co.)
Solutions were prepared in 10 mM MOP buffer (pH 7.0) on a weight / volume basis.

[0093]Strain  E. faecalis, E. faecium and E. gallinarum strains were provided (Merck
Clinical Culture Collection).

[0094]Culture medium  Bacteria maintained on Brain Heart Perfusion (BHI) (Difco) agar slant prior to testing
And grown overnight in BHI broth (Difco). The test medium used was HBI broth
Met.

[0095]MIC measurement  The MIC was measured by broth microdilution. B serial dilutions of each antibiotic
Prepared in HI broth, about 10⁶Inoculated at CFU / mL. MIC is 35 ° C 22
Minimum antibiotic concentration at which there is no visible growth after incubation for hours
Is defined as degrees.

[0096]Crossover and time-disinfection synergy test  Serial two-fold antibiotic dilutions were prepared in BHI broth, and⁶Contact at CFU / mL
Seeded. Follow-up time-Disinfection test was performed in the flask. Hula containing BHI broth
Compound A or a combination of compound A and gentamicin in a flask (50 mL / flask)
(At clinically relevant concentration) and inoculate at about 106 CFU / mL, 85 rp
and incubated at 35 ° C. with shaking. Survival counts on BHI agar plates
At appropriate time intervals.

[0097]result  FIG. 2 shows that Compound A alone contains Van^RGent^SAmp^SE. faecalis CL52
44 is shown to be effective. However, a certain amount of gentama
The combination of isine and Compound A had a significant synergistic effect.

[0098] Figure 3 is a compound A alone ^Van R Gent ^S Amp ^S E. ^faecalisCL48
77 is shown to be effective. However, the combination of ciprofloxacin and Compound A in certain amounts had a significant synergistic effect.

[Brief description of the drawings]

FIG. 1 shows the effects of various concentrations of Compound A alone and in combination with imipenem (20 mg / kg) in the treatment of VanA-resistant E. faecium CL5053 using a mouse thigh model.

FIG. 2 shows the Van ^R Gent ^S Amp ^S E. faecalis CL5244 kill rates of various concentrations of Compound A alone and in combination with 12 μg / mL gentamicin.

FIG. 3 shows Van ^R Gent ^S Amp ^S E. faecalis CL4877 kill rates of various concentrations of Compound A alone and in combination with 1.0 μg / mL ciprofloxacin.

FIG. 4. Compound A (10 mg / k) in the treatment of VanA resistant E. faecium CL5053.
g) and the effect of various amounts of imipenem and meropenem and the effect of compound A (10 mg / kg) in combination with various amounts of imipenem or meropenem.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/545 A61K 31/7052 31/7052 31/726 31/726 A61P 31/04 A61P 31/04 C07D 487 / 04 134 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, Y, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP , KE, KG, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Gil, Charles J. United States of America, New Jersey 07065, East Lincoln Avenieux 126 (72) Inventor Jackson, Jesse J. United States, New Jersey 07065, East Lincoln Avenille 126 (72) Inventor Kohler, Jyois America United States, New Jersey 07065, East Lincoln Avenille 126 (72) Inventor Silver, Lin Lel United States of America, New Jersey 07065, East Lincoln Avenille 126 F-term (reference) 4C050 KA06 KB04 KB05 KB12 KB13 KB16 4C086 AA01 AA02 AA03 BC29 CC04 CC08 CC12 EA01 EA12 MA01 MA04 MA10 NA14 ZB35 4C206 AA01 AA02 AA03 GA01 GA28 MA01 MA04 MA12 MA18 MA28 NA14 ZB35

Claims (23)

[Claims] 1. A pharmaceutically acceptable carrier; 2- (naphthosultami,
L) Methyl-carbapenem: [Where R¹Represents H or methyl; CO₂M is a carboxylic acid group, carboxylate anion, pharmaceutically acceptable
Represents a carboxylic acid group protected by an ester group or a protecting group; P represents hydrogen, a hydroxyl group, F or a hydroxyl group protected by a hydroxyl protecting group; each R independently represents -R^*-Q; hydrogen; halogen; -CN;₂; -NR^a R^b; -OR^c; -SR^c; -C (O) NR^aR^b; -C (O) OR^h; -S (
O) R^c; -SO₂R^c; -SO₂NR^aR^b; -NR^aSO₂R^b; -C (O
) R^a; -OC (O) R^a; -OC (O) NR^aR^b; -NR^aC (O) NR^b R^c; -NR^aCO₂R^h; -OCO₂R^h; -NR^aC (O) R^b; Unsubstituted
Or 1 to 4 R^d-Or branched -C substituted with a group_1-6Alkyl;
And unsubstituted or 1-4 R^d-C substituted with a group_3-7Cycloalkyl
Selected from; each R^a, R^bAnd R^cIs independently hydrogen; -R^*, Unsubstituted or 1-4
R^d-Or branched -C substituted with a group_1-6Alkyl; or if unsubstituted
Or 1 to 4 R^d-C substituted with a group_3-7Represents cycloalkyl; or
Is R^aAnd R^bAnd 1 to 3 O, S, NR^cBy
Represents a 4- to 6-membered saturated ring which may be interrupted;^cIs as defined above
—C (O) —; the ring is unsubstituted or has 1 to 4 RⁱSubstituted with a group
Or R^bAnd R^cAnd one or more O, S, NR together with the intervening atom^aInterrupted by
Represents a 4- to 6-membered saturated ring which may be substituted;^aIs as defined above-
The ring is unsubstituted or 1 to 4 RⁱEach R^dIs independently halogen; -CN; -NO₂; -NR^eR^f; -OR^g;-
SR^g; -CONR^eR^f; -COOR^g; -SOR^g; -SO₂R^g; -SO ₂ NR^eR^f; -NR^eSO₂R^f; -COR^e; -NR^eCOR^f; -OCO
R^e; -OCONR^eR^f; -NR^eCONR^fR^g; -NR^eCO₂R^h;-
OCO₂R^h; -C (NR^e) NR^fR^g; -NR^eC (NH) NR^fR^g;-
NR^eC (NR^f) R^g; -R^*Or -Q; R^e, R^fAnd R^gIs hydrogen; -R^*Unsubstituted or 1-4 RⁱBased on
Substituted straight-chain or branched -C_1-6Represents alkyl; or R^eAnd R^fAnd 1-3 atoms of O, S, -C (O)-or
Is NR^gRepresents a 4-6 membered saturated ring optionally interrupted by^gIs above
As defined; the ring is unsubstituted or has 1 to 4 RⁱEach RⁱIs independently halogen; -CN; -NO₂Phenyl; -NHSO₂R^h ; -OR^h; -SR^h; -N (R^h)₂; -N⁺(R^h)₃; -C (O) N (R ^h )₂; -SO₂N (R^h)₂Heteroaryl; heteroarylium; -CO ₂ R^h; -C (O) R^h; -OCOR^h; -NHCOR^hGuanidinyl; cal
Bamimidyl; or represents ureido; each R^hIs independently hydrogen, linear or branched -C_1-6Alkyl group, -C_{3- 6} R represents a cycloalkyl group or phenyl;^hThere are two groups
If those R^hOne or two O, S, SO₂, −
C (O)-, NH and NCH₃4-6 member saturation that may be interrupted by
Q can be selected from the group consisting of: embedded image a and b are 1, 2 or 3; L⁻Is a pharmaceutically acceptable counterion; α is O, S or NR^sRepresents β, δ, λ, μ and σ are CR^t, N or N⁺R^sWhere N⁺R ^s Is not more than one of β, δ, λ, μ and σ; R^*IsIs selected from the group consisting of: d is O, S or NR^kE, g, x, y and z are CR^m, N or N⁺R^kWhere N⁺R ^k Is no more than one of e, g, x, y and z; R^kIs hydrogen; unsubstituted or 1-4 RⁱStraight or branched substituted with a group
C_1-6Alkyl; or-(CH₂)_nQ (n = 1, 2 or 3;
Q is as defined above); each R^mIs independently hydrogen; halogen; -CN; -NO₂; -NRⁿR^o; -OR ⁿ ; -SRⁿ; -CONRⁿR^o; -COOR^h; -SORⁿ; -SO₂Rⁿ;
-SO₂NRⁿR^o; -NRⁿSO₂R^o; -CORⁿ; -NRⁿCOR^o;-
OCORⁿ; -OCONRⁿR^o; -NRⁿCO₂R^h; -NRⁿCONR^oR ^h ; -OCO₂R^h; -CNRⁿNR^oR^h; -NRⁿCNHNR^oR^h; -N
RⁿC (NR^o) R^hUnsubstituted or 1-4 RⁱStraight chain substituted with a group
-B of branch_1-6Alkyl; unsubstituted or 1-4 RⁱSubstituted with a group
Linear or branched -C_3-7Cycloalkyl; or-(CH₂)_nQ (n
And Q are as defined above); RⁿAnd R^oIs hydrogen, phenyl; unsubstituted or 1-4 RⁱSubstituted with a group
Straight-chain or branched -C_1-6Represents an alkyl; each R^sIs independently hydrogen; unsubstituted or 1-4 RⁱSubstituted with phenyl
Or a linear or branched -C_1-6Represents an alkyl; each R^tIs independently hydrogen; halogen; phenyl; -CN;₂; -NR^uR ^v ; -OR^u; -SR^u; -CONR^uR^v; -COOR^h; -SOR^u; -S
O₂R^u; -SO₂NR^uR^v; -NR^uSO₂R^v; -COR^u; -NR^uC
OR^v; -OCOR^u; -OCONR^uR^v; -NR^uCO₂R^v; -NR^uC
ONR^vR^w; -OCO₂R^vUnsubstituted or 1-4 RⁱSubstituted with a group
Linear or branched -C_1-6R represents alkyl;^uAnd R^vIs hydrogen or unsubstituted or 1-4 RⁱSubstituted with a group
Linear or branched -C_1-6Represents alkyl; or R^uAnd R^vAnd one or more O, S, NR together with the intervening atom^wOr -C
Represents a 4- to 6-membered saturated ring which may be interrupted by (O)-;
Or 1 to 4 RⁱEach R^wIs independently hydrogen; unsubstituted or 1-4 RⁱDirectly substituted with a group
Chain or branched -C_1-6Alkyl; 1-4 RⁱMay be substituted with a group
C_3-5Cycloalkyl; 1-4 RⁱOptionally substituted with a group
Or 1-4 RⁱRepresents heteroaryl optionally substituted with a group;
Or R^hAnd R^wAnd one or two O, S, SO₂, N
H or NCH₃Represents a 5-6 membered saturated ring optionally interrupted by^xIs hydrogen or one or two O, S, SO, SO₂, NR^w, N⁺ R^hR^wOr a straight or branched chain which may be interrupted by -C (O)-
C_1-8Alkyl; the alkyl chain is unsubstituted or has 1 to 4 halogen atoms;
, CN, NO₂, OR^w, SR^w, SOR^w, SO₂R^w, NR^hR^w, N⁺ (R^h)₂R^w, -C (O) -R^w, C (O) NR^hR^w, SO₂NR^hR^w,
CO₂R^w, OC (O) R^w, OC (O) NR^hR^w, NR^hC (O) R^w, N
R^hC (O) NR^hR^wOr substituted with phenyl or heteroaryl
Said phenyl or heteroaryl has 1 to 4 RⁱGroup or 1-2
Linear or branched C_1-3An alkyl group (the alkyl group is unsubstituted or
RⁱR.^yAnd R^zIs hydrogen; phenyl; unsubstituted or 1-4 RⁱSubstitute with group
O, S, NR^w, N⁺R^hR^wOr interrupted by -C (O)-
Linear or branched -C which may be_1-6Represents alkyl; or R^yAnd R^zTogether with the intervening atoms, O, S, SO₂, NR^w, N⁺R^h R^wOr a 4- to 6-membered saturated ring which may be interrupted by -C (O)-
The ring is unsubstituted or has 1 to 4 RⁱR;^xAnd R^yAnd when taken together represent a 4- to 6-membered ring as defined above,^zIs
As defined above, or R^zIs an integrated R^xAnd R^yBy
Represented O, S, NR^wOr to a ring which may be interrupted by -C (O)-
Represents another saturated 4- to 6-membered ring fused; the rings may be unsubstituted or 1 to 4 R ⁱ Substituted with a group. And carbapenems, cephalosporins (ceftriaxone), penici
Phosphorus; aminoglycosides (eg, gentamicin and amikacin, dibeca)
Syn, streptomycin, neomycin, kanamycin, spectinomycin
, Kasugamycin, etc., but not limited thereto);
(Eg, ciprofloxacin and trovafloxacin),
Sparfloxacin, gatifloxacin,
Grepafloxacin, ofloxacin, norfloxacin,
Loxin, levofloxacin, etc. (limited to these
)) And related quinolones having activity against topoisomerase
And naphthyridines; chloramphenicol; and macrolides, ketori
, Azalides, sinacid (registered trademark), tetracyclines (glycylsa
Ecrins), glycopeptides (vancomycin, teicoprinin, LY-
333328), novobiocin (and coomamycin) and oxazoly
An antibiotic composition comprising another antibiotic such as a dinone or a combination thereof. 2. The compound of formula I wherein the compound of formula I is represented by the following formula Ie:
Or a pharmaceutically acceptable salt thereof. Embedded image Wherein R is -R^*, Q and one R^dStraight or branched, substituted by a group
C_1-6Having a positively charged moiety selected from the group consisting of alkyl chains; Rd is independently -R^*Or Q is selected from: Q is selected from the group consisting of: Where L⁻, A and b are as defined above; R^xIs hydrogen or 1
Or two O, S, SO, SO₂, NR^w, N⁺R^hR^wOr -C (
O)-a linear or branched C which may be interrupted by-_1-8Alkyl
A moiety selected from the group consisting of: unsubstituted or 1-4 alkyl chains.
Halogen, CN, NO₂, OR^w, SR^w, SOR^w, SO₂R^w, NR^hR ^w , N⁺(R^h)₂R^w, -C (O) -R^w, C (O) NR^hR^w, SO₂NR ^h R^w, CO₂R^w, OC (O) R^w, OC (O) NR^hR^w, NR^hC (O)
R^w, NR^hC (O) NR^hR^wOr a phenyl or heteroaryl group
Substituted; the phenyl or heteroaryl has 1 to 4 RⁱBase
Represents one or two linear or branched C_1-3An alkyl group (the alkyl group is unsubstituted
There are 1 to 4 RⁱR.^*Is selected from the following: Where d is NR^kR;^kIs a linear or branched -C_1-6Table showing alkyl
E, g, x and y are CR^mOr N⁺R^kAnd R^kIs defined above
And R^mRepresents hydrogen. ] 3. A compound of the formula I wherein (1S, 5R, 6S) -2- (5-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-) Yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (5-(((3-hydroxyprop-1-yl)
-1,4-diazoniabicyclo [2.2.2] oct-1-yl) methyl) (1
, 8-Naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-
Methylcarbapene-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (5-((1-methylimidazole-3-ium) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate; (1S, 5R, 6S) -2- (5-(((2- (1-methyl Imidazole-3
-Ium) -ethyl) (1,8-naphthosultam) methyl) -6- [1 (R)-
(Hydroxyethyl) -1-methylcarbapene-2-em-3-carboxylate; (1S, 5R, 6S) -2- (4-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2] .2] oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl) -1,
4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,
8-Naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (4- ( 2-(((3-hydroxyprop-1-
Yl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1 -Methylcarbapene-2-em-3-carboxylate chloride;
Or (1S, 5R, 6S) -2- (4- (2-((1-methylimidazole-3-
2. The composition according to claim 1, wherein the composition is (ium) -ethyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate. object. 4. A compound of the formula I wherein (1S, 5R, 6S) -2- (5-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-) Yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; (1S, 5R, 6S) -2- (4-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 ( (R) -hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate chloride; or (1S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl) -1,
4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,
8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride.
A composition according to claim 1. 5. The method of claim 1, wherein said other antibiotic is selected from the group consisting of cephalosporins, penicillins, gentamicin, ciprofloxacin, imipenem, meropenem, chloramphenicol, vancomycin, or teicoprimin. A composition according to claim 1. 6. A pharmaceutically acceptable carrier; a therapeutically effective amount of (1S, 5R, 6S) -2- (5-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2. 2] oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; 1S, 5R, 6S) -2- (4-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl) methyl) (1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; and (1S, 5R, 6S) -2- (4- (2-((( Carbamoylmethyl) -1,
4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,
2- (naphthosultamyl) methyl-carbapenem selected from 8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; and carbapenem , Cephalosporins, penicillins; gentamicin, amikacin, dibekacin,
Aminoglycosides such as streptomycin, neomycin, kanamycin, spectinomycin, kasugamycin; fluo such as ciprofloxacin, trovafloxacin, sparfloxacin, gatifloxacin, grepafloxacin, ofloxacin, norfloxacin, floxin, levofloxacin, etc. Quinolones; quinolones, naphthyridines, chloramphenicol, macrolides, ketolides, azalides, cinnaside (registered trademark), tetracyclines, glycylcyclines; An antibiotic composition comprising a therapeutically effective amount of another antibiotic selected from novobiocin, coomamycin and oxazolidinones or a combination thereof. 7. The method according to claim 1, wherein the 2- (naphthosultamyl) methyl-carbapenem is (1)
S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8 -Naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride; the other antibiotics are cephalosporins, penicillins Gentamicin, ciprofloxacin, meropenem, imipenem, (4R, 5S, 6S) -3-[(3S, 5S)
-5- (3-Carboxyphenylcarbamoyl) pyrrolidin-3-ylthio]-
6- (1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid, chloramphenicol, vancomycin and teicoply 7. The composition according to claim 6, wherein the composition is selected from nin. 8. The antibiotic composition according to claim 1, wherein said other antibiotic is carbapenem. 9. The carbapenem wherein about 1 to about 100 mg / kg of imipenem, (4R, 5S, 6S) -3-[(3S, 5S) -5- (3-carboxyphenylcarbamoyl) pyrrolidin-3-ylthio] -6- (1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-
2-ene-2-carboxylic acid or meropenem; wherein said 2- (naphthosultamyl) methyl-carbapenem is from about 0.1 to about 50 mg / kg of (1S, 5R, 6S).
) -2- (4- (2-(((Carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8-naphthosultam)
Methyl) -6- [1 (R) -hydroxyethyl] -1-methylcarbapene-2-
9. The composition according to claim 8, which is em-3-carboxylate chloride. 10. Imipenem, (4R, 5S, 6S) -3-[(3S, 5S
) -5- (3-Carboxyphenylcarbamoyl) pyrrolidin-3-ylthio]
-6- (1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid or meropenem is present in an amount of about 2 to about 50 mg / kg; (1S, 5R, 6S) -2- (4- (2-
(((Carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8-naphthosultam) methyl) -6- [1 (
The composition of claim 9, wherein the amount of (R) -hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride is from about 0.5 to about 20 mg / kg. 11. A pharmaceutically acceptable carrier; about 2 to about 50 mg / kg of imipenem; a pharmaceutically acceptable amount of cilastatin; and about 0.5 to about 20 mg.
/ Kg of (1S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl)
-1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl)
(1,8-naphthosultam) methyl) -6- [1 (R) -hydroxyethyl]-
An antibiotic composition comprising 1-methylcarbapene-2-em-3-carboxylate chloride. 12. The composition according to claim 11, wherein said imipenem and cilastatin are administered as Primaxin®. 13. The antibiotic composition according to claim 1, wherein said other antibiotic is fluoroquinolone, aminoglycoside, chloramphenicol or a combination thereof. 14. The fluoroquinolone is about 0.1 to about 40 mg / kg ciprofloxacin, and the aminoglycoside is about 0.5 to about 12 mg / kg.
Wherein the 2- (naphthosultamyl) methyl-carbapenem is from about 0.1 to about 50 mg / kg of (1S, 5R, 6S) -2- (4- (2-((
(Carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-
1-yl))-ethyl) (1,8-naphthosultam) methyl) -6- [1 (R)
-Hydroxyethyl] -1-methylcarbapene-2-em-3-carboxylate chloride. 15. The method according to claim 15, wherein the amount of ciprofloxacin is about 0.5 to about 20 mg / kg, and (1S, 5R, 6S) -2- (4- (2-(((carbamoylmethyl)-
1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (
1,8-Naphthosultam) methyl) -6- [1 (R) -hydroxyethyl] -1
The amount of methylcarbapene-2-m-3-carboxylate chloride is about 0;
. 15. The composition of claim 14, wherein the composition is between 5 and about 20 mg / kg. 16. A pharmaceutically acceptable carrier; about 0.5 to about 20 mg / kg ciprofloxacin or about 0.5 to about 12 mg / kg gentamicin; and about 0.5 to about 20 mg / kg. (1S, 5R, 6S) -2- (4- (2- (
((Carbamoylmethyl) -1,4-diazoniabicyclo [2.2.2] oct-1-yl))-ethyl) (1,8-naphthosultam) methyl) -6- [1 (R
) -Hydroxyethyl] -1-methylcarbapen-2-em-3-carboxylate chloride. 17. Imipenem, (4R, 5S, 6S) -3-[(3S, 5S
) -5- (3-Carboxyphenylcarbamoyl) pyrrolidin-3-ylthio]
-6- (1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid or meropenem and cephalosporins; In combination with another antibiotic selected from penicillins, gentamicin, ciprofloxacin, chloramphenicol, vancomycin or teicoprinin, a 2- (naphthosultamyl) methyl-carbapenem antibacterial agent or an ophthalmically acceptable agent thereof A composition according to claim 1, comprising a salt to be prepared. 18. A method of treating or preventing a bacterial infection in a mammalian patient in need of treatment, comprising administering to said patient an effective amount of the composition of claim 1. 19. A method of treating or preventing enterococcal or MRSA infection, comprising administering a unit dose of the composition of claim 1 to a patient in need of such treatment. . 20. A method of treating or preventing enterococcal or MRSA infection, comprising administering a unit dose of the composition of claim 6 to a patient in need of such treatment. . 21. A method of treating or preventing enterococcal or MRSA infection, comprising administering a unit dose of the composition of claim 11 to a patient in need of such treatment. . 22. A method of treating or preventing an enterococcal or MRSA infection, comprising administering a unit dose of the composition of claim 14 to a patient in need of such treatment. . 23. A method of treating or preventing enterococcal or MRSA infection, comprising administering a unit dose of the composition of claim 16 to a patient in need of such treatment. .